(a) Field of the Invention
The present invention relates to pharmaceutical agents (compounds) which act as leukotriene B.sub.4 (LTB.sub.4) antagonists in mammals. The compounds of the present invention are useful in treating inflammatory conditions in mammals such as psoriasis, Crohn's disease, ulcerative colitis and the like.
(b) Prior Art
LTB.sub.4 (Formula I) is an arachidonic acid metabolite which is produced by the 5-lipoxygenase pathway. Pharmacologically, LTB.sub.4 is an important mediator of inflammation in mammals. As a mediator of inflammation, LTB.sub.4 is known to induce chemotaxis, chemokinesis, aggregation, and degranulation of leukocytes in vitro, and to induce accumulation of polymorphonuclear leukocytes, and increase vascular permeability and edema formation in vivo. ##STR3##
Particularly high levels of LTB.sub.4 are detected in lesions in inflammatory diseases such as rheumatoid or spondylarthritis, gout, psoriasis, ulcerative colitis, Crohn's disease, and some respiratory diseases.
Accordingly, it is an object of this invention to produce compounds for use as pharmaceutical agents which will exhibit LTB.sub.4 antagonist activity in mammals.
A potential LTB.sub.4 antagonist (Formula II), which is structurally different from the compounds of the present invention, is disclosed in Biochem. and Biophys. Res. Comm., 138 540-546 (1986). ##STR4##
In this article, the authors also suggest that they have found antagonistic activity in a series of unidentified unsaturated dihydroxy fatty acid derivatives which are to be the subject of a future publication.
Furber, et al., disclose the preparation of LTB.sub.4 analogues of Formulas III-V wherein phenyl or pyridyl ring provides the trans, trans double bonds corresponding to C-8 and C-10 trans trans double bonds in naturally occurring LTB.sub.4. J. Chem. Soc. Perkin Trans. I, 7 1573 (1987). ##STR5##
The pharmacology of the biologically active leukotrienes is generally discussed in J. Clin. Invest. 73, 889-897 (1984).